The cutaneous vasculature is present in the dermis and is composed of blood vessels and lymph vessels. In order to maintain homeostasis, tissue fluid that has migrated outside blood vessels must be recirculated to veins. Veins present in skin effectively send blood to the body's core. However, veins per se lack the ability to incorporate tissue fluid. On the basis of this as well, tissue that incorporates tissue fluid, namely lymph vessels, have come to be understood to be an essential structure in the skin as well.
Lymph vessels fulfill an important role in order to maintain the microenvironment surrounding tissue in a constant state by recovering unwanted substances present in skin as well as water and protein constantly escaping from blood vessels. In addition, it has also come to be thought to fulfill the role of demonstrating resistance to infectious factors and external factors from the outside world by mediating the transport of T lymphocytes.
Known examples of pathological states associated with lymph vessel dysfunction include symptoms such as swelling and lymphedema (Non-Patent Document 1: Jusilla, L. & Alitalo, K. (2002), Physiol. Rev. 82, 673-700). In addition, lymph vessel function has also been determined to fulfill an important role in not only swelling, but also photoaging (wrinkle formation) of skin accompanying exposure to ultraviolet rays (Non-Patent Document 2: Kajiya, K. & Detmar, M. (2006), J. Invest. Dermatol. 126, 919-21).
According to previous research, VEGFR-3 has been identified as a transmembrane receptor specifically present in lymph vessels, and VEGFC and VEGFD have been found to be ligands thereof. VEGFC activates the function of lymph vessels by promoting the proliferation, migration and lumen formation of lymphatic endothelial cells by acting on lymph vessels (Non-Patent Document 1: Jusilla, L. & Alitalo, K. (2002), Physiol. Rev. 82, 673-700). In addition, possibilities are being sought for gene therapy involving the application of VEGFC to the pathological state of swelling in the form of edema (Non-Patent Document 3: Saaristo, A., Tammela, T., Timonen, J., Yla-Herttuala, S., Tukianen, E., Asko-Seljavaara, S. & Alitalo, K. (2004), Faseb. J. 18, 1707-9).
Recently, mutant mice having a genetic mutation that causes lymph vessel dysfunction are known to exhibit obesity as they mature. Findings have been obtained regarding the mechanism by which abnormalities in lymph vessel formation and function result in obesity that indicate that lymphatic fluid flowing through lymph vessels promotes differentiation of mast cell progenitors into fat (Patent Document 4: Harvey, N. L., et al., Nat. Genet. 2005, 37, 1072-81). In other words, functional abnormalities of lymph vessels have been reported to cause escape of lymphatic fluid outside lymph vessels leading to differentiation into fat and eventually the onset of obesity. Thus, VEGFC promoter is expected to function as an obesity preventive or therapeutic agent that functionally regenerates lymph vessels.
The VEGF gene family consists of VEGF-A through VEGF-E. Among these, VEGFB and VEGFE have been identified as factors that act only on blood vessels. Although VEGFA is present in the skin and acts on lymph vessels, it is known to be a factor that conversely exacerbates the function of lymph vessels (Non-Patent Document 5: Nagy, J. A., Vasile, E., Feng, D., Sundberg, C., Brown, L. F., Detmar, M. J., Lawitts, J. A., Benjamin, L., Tan, X., Manseau, E. J., Dvorak, A. M. & Dvorak, H. F. (2002), J. Exp. Med. 196, 1497-506).
In the skin, although VEGFD has been reported to be present in trace amounts in the dermis, since VEGFD knockout mice do not exhibit any formational or functional abnormalities of skin lymph vessels whatsoever, VEGFD is not thought to be a factor that is essential for lymph vessel formation in skin (Non-Patent Document 6: Baldwin, M. E., Halford, M. M., Roufail, S., Williams, R. A., Hibbs, M. L., Grail, D., Kubo, H., Stacker, S. A. & Achen, M. G. (2005), Mol. Cell. Biol. 25, 2441-9). On the other hand, VEGFC in the skin is strongly expressed in the epidermis. Mice in which VEGFC has been strongly expressed in the epidermis exhibit an increase in the number of lymph vessels present in the dermis (Non-Patent Document 7: Jeltsch, M., Kaipeinen, A., Joukov, V., Meng, X., Lakso, M., Rauvala, H., Swartz, M., Fukumura, D., Jain, R. K. & Alitalo, K. (1997), Science 276, 1423-5), while on the other hand, when the effects of VEGFC in the epidermis were blocked by highly expressing neutralizing antibody of a VEGFC receptor in the form of VEGFR-3 in the epidermis, findings were obtained that indicated a dramatic decrease in the number of lymph vessels in the dermis along with the onset of edema (Non-Patent Document 8: Makinen, T., Jussila, L., Veikkola, T., Karpanen, T., Kettunen, M. I., Pulkkanen, K. J., Kauppinen, R., Jackson, D. G., Kubo, H., Nishikawa, S., Yla-Herttuala, S. & Alitalo, K. (2001), Nat. Med. 7, 199-205). On the basis thereof, it has been determined that the function of lymph vessels present in skin dermis is controlled by VEGFC expressed in the epidermis, and that swelling (edema) occurs as a result of VEGFC no longer functioning.
It has been previously reported that specific terpenoids and derivatives thereof have a VEGF production-promoting action and are useful as wound healing agents, hair restorers and hair growth agents and external skin agents having ameliorative effects on skin color (Patent Document 1), and that plant extracts in the manner of apricot kernel extract, ginseng extract, Japanese valerian extract, crataegus fruit extract, melilot extract, white nettle extract and orris root extract have VEGFC production-promoting action (Patent Document 2).